Helicobacter pylori chronically colonizes over half of the world's human population and causes diseases such as gastritis, ulcer disease and gastric carcinoma. H. pylori colonizes within the stomach, where it encounters large fluctuations in pH, iron availability and other environmental factors. Because of this dynamic niche and due to H. pylori's high success rate in long-term colonization, the bacterium must be adept at regulating gene expression. We previously showed that expression of the gene that encodes the Ferric Uptake Regulator (Fur) was altered upon exposure of H. pylori to acidic pH and upon iron limitation. Thereafter, our and other groups have shown that Fur is a crucial regulatory factor that is required for survival of H. pylori at low pH, upon nutrient (iron) deprivation, and within oxidative, nitrosative and osmotic stress conditions. Moreover, and perhaps most importantly, we have shown that Fur-mediated regulation is crucial for H. pylori colonization and disease; Fur mutant strains show altered dynamics of colonization in the gerbil model of infection as well as significant attenuation in development of inflammation and gastric cancer. Additionally, our subsequent studies suggest that the effect on disease may be due to a role for Fur in activation of expression of cagA, which encodes a type IV secreted effector protein that is crucial for cancer development. Herein, we propose to characterize the process of Fur-mediated activation of expression of cagA and examine expression and delivery of CagA in vivo, define the role of identified Fur-regulated genes in stress adaptation, colonization and disease development and to determine the role of Fur in expression of H. pylori small RNA (sRNA) species as well as the contribution of these sRNA species to gene expression. We predict that our work will continue to shed significant insight into the process by which gene regulation is mediated in H. pylori as well as help to define how adaptation relates to infection and ultimate disease development by this important human pathogen. These studies will fill a fundamental gap in knowledge concerning the process of adaptation and regulation in H. pylori and should provide potential new therapeutic targets for H. pylori.